This project tests the hypothesis that the process that leads to disease susceptibility, disability and frailty in older persons largely constitutes a progressive dysregulation and reduced reserve capacity in the network of biological mechanisms that interact to maintain a stable energetic homeostasis and/or a defect or deficiency in the capacity to regain equilibrium when homeostasis is critically challenged by a stressful event. Elements comprising these networks are not completely defined but certainly include: 1. Intake of essential elements the body requires to create energy, including both nutrients and oxygen; 2. Activities that affect the different forms of energy utilization, including resting metabolic rate, physical activity, cognitive activity and nutrition; 3. Neurological control of energy flow, mostly affected by the interplay between the sympathetic and the parasympathetic nervous systems; 4. The endocrine system, which is also in charge of modulating the locoregional distribution of energy flow, but acts more slowly than the autonomic nervous system; 5. The production of Oxygen Free Radicals (ROS) during aerobic metabolism has important signaling properties but can also produce large damage to several macromolecules; 6. Ultimately, any type of damage triggers an inflammatory response, which in turn diverts energy utilization to the function(s) necessary for or in need of repair. Several biomarkers of the capacity and/or performance of these six systems have been developed over the last several years and some use high throughput assays that allow utilization in epidemiological studies. However, no current study has the broad range of information required to address the multysistem dysregulation hypothesis in an epidemiological setting. Therefore, we have identified several studies that include a subset of these measures that can be used to test one or more partial components of our general hypothesis. By creating a network of collaborations with the research groups conducting these studies, we have gained access to data that complement those that we already collect in the BLSA. In particular, in the context of this project, we intend to use data from: a. The Baltimore Longitudinal Study of Aging b. The InChianti Study c. The SardiNIA study d. The Women's Health and Aging Study e. The Health ABC Study f. The ICare/Dicomano Study g. The ASSI Italian Initiative h. The ILSA Study i. The Il Sirente Study l. The AGES study Collaborations between the LSS and investigators of these studies have been established. Other studies may be added to this initiative, based on opportunities and needs of the research group. In the intial period of this project, we continue to test the hypothesis of an independent correlation between the different homeostatic domains and their association with geriatric-relevant outcomes, such as morbidity, frailty, disability and mortality. In the second phase, we are studying the effects on similar outcomes of multiple biomarkers and physiological measures, within a specific domain and across different domains. The second part of this project requires some methodological and statistical development. This methodological component is considered an essential component of the project and will be conducted in collaboration with multiple academic institutions.